The current proposal focuses on the concept that thyroid hormone activation (T4 to T3 conversion) via the type 2 deiodinase (D2)plays a critical role in fuel homeostasis and energy expenditure. This concept originated from studies in brown adipose tissue (BAT), the main thermogenic tissue in human newborns and other small mammals. Recently, the discovery of D2 activity in human skeletal muscle has generated considerable excitement as it has become clear that deiodination is a common mechanism for metabolic control (1).Given this background, we were immediately intrigued by fact that BAT D2 is up-regulated in a mouse model of resistance to diet-induced obesity. In this model, supplementation with 0.5% bile acids prevents animals from becoming overweight or insulin-resistant when placed on a high fat diet. Intense collaborative investigation resulted in the first recognition of an FXR-independent metabolic pathway through which bile acids interact with the G-protein coupled receptor TGR5 and thus stimulate D2 in metabolically relevant tissues including BAT and human skeletal myocytes. Our preliminary studies indicate that other ; GPCRs also stimulate D2. These striking data suggest that the spectrum of metabolites controlling D2, and the range of target tissues in which this mechanism is operant may be even more extensive than previously thought. With this in mind, we have begun to search for novel D2-regulating substances, and have preliminary evidence supporting significant regulatory effects for xenobiotic compounds. Understanding how metabolic signals from rapidly fluctuating endogenous molecules and xenobiotic factors are integrated via the D2 pathway is the major goal of these studies. Ultimately, by understanding these novel mechanisms for thyroid-hormone dependent metabolic control, we hope to identify new targets and approaches for therapeutic intervention in metabolic disorders including type II diabetes, obesity, and the metabolic syndrome.